Water soluble derivatives of p-aminobenzenesulphonamide



Patented Dec. 5, 1939 WATER SOLUBLE DERIVATIVES FP-AMINOBENZENESULPHONAMIDE Joseph Ebert, Westmont, N. J assignor to TheFarastan Company, Philadelphia, Pa., a corporation of Pennsylvania NoDrawing. v Original application September 15,

1937, Serial No. 163,915.

Divided and this application July 23, 1938, Serial No. 221,007

9 Claims. (Cl. 260-501) This invention relates to new derivatives ofp-amino-benzenesulphonamide. It relates more particularly to salts ofp-aminobenzenesulphonamide with aromatic sulphonic acid compounds '5selected from the group consisting of phenolsulphonic acid,benzenesulphonic acid and sulphosalicylic acid, which salts are readilysoluble in water and hence are advantageous in therapeutics for thetreatment of various infections 10' caused by cocci.

This application is a division of my copending application, Serial No.163,915, filed Sep-' tember 15, 1937. I

p-Aminobenzenesulphonamide has been recll ognized as having great valuefor the treatment of coccus infections; but its use has been subject toserious disadvantages in view of its slight solubility in water,approximately one part of this compound being soluble in 160 parts ofwater at 20 25 C. Because of this low solubility, the oraladministration of the compound in aqueous solution is impractical, sothat the compound is ordinarily administered orally in tablet form. Thislow solubility is even more objectionable when 5 the compound is used ininjection therapy, as

it has-been found that toobtain therapeutic results, for example, fortreating meningococcic infections, as much as 0.08 to 0.24 gram of thesubstance must be injected intraspinally, re- 30 quiring the injectionof as much as to 30 cc. of liquid. For effective therapeutic resultswith subcutaneous injection, from 0.8 to 3.2 grams of the material mustbe injected every twelve hours, requiring the subcutaneous injection offrom 100 35 to 400 cc. of solution. Injections of such large amounts ofliquid are impractical and often dangerous.

In accordance with the present invention, derivatives ofp-aminobenzenesulphonamide, char- 40 acterized by ready solubility inwater are prepared. The nature of these new salts is such that whenadministered they readily split to reform the p-aminobenzenesulphonamideand the acid, thus retaining the therapeutic properties 45 of thep-aminobenzenesulphonamide with the attendant advantages due to readysolubility in water, which include oral administration in dissolved formusing relatively little water, injection of therapeutic doses withoutincluding 0b- 50 jectionable quantities of liquid, and improvedassimilation and faster circulation.

mgh solubility in water is one of the important characteristics of thecompounds of the invention and I have found it important to usesulphonic 55 acids which form salts with p-aminobenzenesulphonamidehaving a solubility in water greater than 1 to 20; in other words, asolubility such that one part of the salt is soluble in less than twentyparts of water.

Among the sulphonic acids which I have found 6 to be particularlyadvantageous for use are the sulphonic acids of benzene, phenol andsalicylic acid, that is benzenesulphonic acid, phenolsulphonic andsulphosalicylic acid. Each of these compounds forms a salt withp-aminobenzene- 10 sulphonamide having a solubility in Water greaterthan 1 to 20, and containing approximately 40 to 50% ofp'aminobenzenesulphonamide, such that therapeutic doses of these saltsmay be readily administered, either orally or byinjection, in aqueoussolution without administration of excess or objectionable quantities ofliquid.

These compounds, that is, the new salts, also have other valuableproperties therapeutically. When administered, the compounds break up toform the p-amihobenzenesulphonamide and the sulp-honic acids. Thesulphonic acids are eliminated through the urinary tract practicallyunchanged, that is, in acid form, while the p-aminobenzenesulphonamideis eliminated in the form of its acetyl derivatives, that is, in coupledform.

As a result, the acidity of the urine is increased,

a factor of great value in the treatment of infections of the genitourinary tract. However, 3 if the solutions are used for injectionpurposes, they are advantageously buffered with one of the commonly usedbuffer salts to adjust the pH of their solution from about 7.0 to about7.4,

to avoid irritation. Such bufiering materials as disodium acid phosphateand sodium borate may be advantageously used for this purpose. Highlyalkaline buffering materials, such as sodium carbonate, should beavoided, as their use might result in the precipitation of thep-aminobenzenesulphonamide.

The invention will be further illustrated by the following specificexamples, which describe the preparation of salts which I have found tobe of particular value, although it is not limited thereto.

Exampl 1.The salt of p-aminobenzenesulphonamide with benzenesulphonicacid. 172 parts of p-aminobenzenesulphonamide and 172.5 parts of a 92.5%pure benzenesulphonic acid (or the equivalent amount of abenzenesulphonic acid of higher or lower purity) are mixed in 5000 partsof distilled water or 2500 parts of methanol. The mixture is stirred forseveral minutes until a complete solution is formed, after which it isset aside for a period of 6 to 12 hours. The solvent is then removed byevaporation, preferably under a vacuum, at low temperature, to insurethe production of a compound. of high purity. If the evaporation iscarried out at atmospheric pressure, a slightly more impure compound isproduced. The salt obtained may be purified by recrystallization fromalcohol or water advantageously with the use of a decolorizing agentsuch as activated carbon, filtrol, etc. The crystals obtained melt at213 to 217 C. with decomposition.

One part of this compound, which contains one molecule of water ofcrystallization removable by prolonged drying in the'vacuum, dissolvesin 14 parts of water at 25 C. and contains 49.4% ofp-aminobenzenesulphonamide.

Example 2.The salts of p-aminobenezenesulphonamide with phenolsulphonicacid. 172

parts of p-aminobenzenesulphonamide are mixed with 588 parts ofcommercially available 30 o-phenolsulphonic acid (or theequivalentamount of o-phenolsulphonic acid of higher or lower purity) in 5000parts of distilled water, or 2000 parts of methanol, with recovery andpurification ofthe salt obtained as in EXample 1. The product melts at216 to 220 C. with decomposition.

One part of this new compound dissolves in 14 parts of water at 25 0.Analysis shows that it contains about 49.7 ofp-aminobenzenesulphonamide, together with a small percentage ofpphenolsulphonic acid.

Example 3.The salt of p-aminobenzenesulphonamide with sulphosalicylicacid. 172

parts of p-aminobenezenesulphonamide are reacted with 218 parts ofanhydrous sulphosalicylic acidin 6500 parts of distilled water or 2500.parts of methanol, with recovery and purification of the salt as inExample 1. The product obtained melts at 214 to 220 C. withdecomposition.

One part of the dried compound of this example dissolves in 16 parts ofwater at 25 C. Analysis shows that it contains 44.1% ofpaminobenzenesulphonamide.

In general, the salts are prepared by reacting 'sulphonic acid,benzenesulphonic the .sulphonic acid' with the p-aminobenZehsulphonamide in a suitable solvent, such as the water or methanol of theexamples, although other solvents, such as ethanol, etc., may be used, i

as the solvent does not enter into the reaction, and merely enables theneutralization reaction to take place.

I claim:

1. As new compounds, salts of, p-aminobenzenesulphonamide with aromaticsulphonic acids selected from the group consisting ofphenolsulphosalicylic acid.

-2. The phenolsulphonate of p-aminobenzenesulphonamide.

3. .The benzenesulphonate of p-aminobenzenesulphonamide.

4. The 'sulphosalicylate of p-aminobenzenesulphonamide.

5; The method of preparing water soluble compounds ofp-aminobenzenesulphonamide which comprises reacting 'p-aminobenzenesulphonamide with an aromatic sulphonic acid selected from the groupconsisting of phenolsulphonic acid, benzenesulphonic acid andsulphosalicylic acid.

acid and 6..The method of preparing a water soluble Q comprises reactingp-aminobenzenesulphonamide.

with an aromatic sulphonic acid selected from the group consisting of.phenolsulphonic acid, benzenesulphonic. acid and sulphosalicylic acid inthe presence of a solvent.

' J OSEPH ElBER-Tl reacting p-aminobenzene--

